Monozygotic twins share the same genotype because they are derived from the same zygote. However, monozygotic twin siblings frequently present many phenotypic differences, such as their susceptibility to disease and a wide range of anthropomorphic features. Recent studies suggest that phenotypic discordance between monozygotic twins is at least to some extent due to epigenetic factors that change over the lifetime of a multicellular organism. It has been proposed that epigenetic drift during development can be stochastic or determined by environmental factors. In reality, a combination of the two causes prevails in most cases. Acute environmental factors are directly associated with epigenetic-dependent disease phenotypes, as demonstrated by the increased CpG-island promoter hypermethylation of tumor suppressor genes in the normal oral mucosa of smokers. Since monozygotic twins are genetically identical they are considered ideal experimental models for studying the role of environmental factors as determinants of complex diseases and phenotypes.